View source for 4jnw


==Bacterially expressed Titin Kinase==
<StructureSection load='4jnw' size='340' side='right'caption='[[4jnw]], [[Resolution|resolution]] 2.06&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4jnw]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JNW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JNW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.06&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4jnw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jnw OCA], [https://pdbe.org/4jnw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jnw RCSB], [https://www.ebi.ac.uk/pdbsum/4jnw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jnw ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/TITIN_HUMAN TITIN_HUMAN] Defects in TTN are the cause of hereditary myopathy with early respiratory failure (HMERF) [MIM:[https://omim.org/entry/603689 603689]; also known as Edstrom myopathy. HMERF is an autosomal dominant, adult-onset myopathy with early respiratory muscle involvement.<ref>PMID:15802564</ref>   Defects in TTN are the cause of familial hypertrophic cardiomyopathy type 9 (CMH9) [MIM:[https://omim.org/entry/613765 613765]. Familial hypertrophic cardiomyopathy is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.<ref>PMID:10462489</ref>   Defects in TTN are the cause of cardiomyopathy dilated type 1G (CMD1G) [MIM:[https://omim.org/entry/604145 604145]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.<ref>PMID:11846417</ref> <ref>PMID:11788824</ref> <ref>PMID:16465475</ref>   Defects in TTN are the cause of tardive tibial muscular dystrophy (TMD) [MIM:[https://omim.org/entry/600334 600334]; also known as Udd myopathy. TMD is an autosomal dominant, late-onset distal myopathy. Muscle weakness and atrophy are usually confined to the anterior compartment of the lower leg, in particular the tibialis anterior muscle. Clinical symptoms usually occur at age 35-45 years or much later.<ref>PMID:12145747</ref> <ref>PMID:12891679</ref>   Defects in TTN are the cause of limb-girdle muscular dystrophy type 2J (LGMD2J) [MIM:[https://omim.org/entry/608807 608807]. LGMD2J is an autosomal recessive degenerative myopathy characterized by progressive weakness of the pelvic and shoulder girdle muscles. Severe disability is observed within 20 years of onset.  Defects in TTN are the cause of early-onset myopathy with fatal cardiomyopathy (EOMFC) [MIM:[https://omim.org/entry/611705 611705]. Early-onset myopathies are inherited muscle disorders that manifest typically from birth or infancy with hypotonia, muscle weakness, and delayed motor development. EOMFC is a titinopathy that, in contrast with the previously described examples, involves both heart and skeletal muscle, has a congenital onset, and is purely recessive. This phenotype is due to homozygous out-of-frame TTN deletions, which lead to a total absence of titin's C-terminal end from striated muscles and to secondary CAPN3 depletion.<ref>PMID:17444505</ref> 
== Function ==
[https://www.uniprot.org/uniprot/TITIN_HUMAN TITIN_HUMAN] Key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The size and extensibility of the cross-links are the main determinants of sarcomere extensibility properties of muscle. In non-muscle cells, seems to play a role in chromosome condensation and chromosome segregation during mitosis. Might link the lamina network to chromatin or nuclear actin, or both during interphase.<ref>PMID:9804419</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Striated muscle tissues undergo adaptive remodelling in response to mechanical load. This process involves the myofilament titin and, specifically, its kinase domain (TK; titin kinase) that translates mechanical signals into regulatory pathways of gene expression in the myofibril. TK mechanosensing appears mediated by a C-terminal regulatory tail (CRD) that sterically inhibits its active site. Allegedly, stretch-induced unfolding of this tail during muscle function releases TK inhibition and leads to its catalytic activation. However, the cellular pathway of TK is poorly understood and substrates proposed to date remain controversial. TK's best-established substrate is Tcap, a small structural protein of the Z-disc believed to link TK to myofibrillogenesis. Here, we show that TK is a pseudokinase with undetectable levels of catalysis and, therefore, that Tcap is not its substrate. Inactivity is the result of two atypical residues in TK's active site, M34 and E147, that do not appear compatible with canonical kinase patterns. While not mediating stretch-dependent phospho-transfers, TK binds the E3 ubiquitin ligase MuRF1 that promotes sarcomeric ubiquitination in a stress-induced manner. Given previous evidence of MuRF2 interaction, we propose that the cellular role of TK is to act as a conformationally regulated scaffold that functionally couples the ubiquitin ligases MuRF1 and MuRF2, thereby coordinating muscle-specific ubiquitination pathways and myofibril trophicity. Finally, we suggest that an evolutionary dichotomy of kinases/pseudokinases has occurred in TK-like kinases, where invertebrate members are active enzymes but vertebrate counterparts perform their signalling function as pseudokinase scaffolds.

Titin kinase is an inactive pseudokinase scaffold that supports MuRF1 recruitment to the sarcomeric M-line.,Bogomolovas J, Gasch A, Simkovic F, Rigden DJ, Labeit S, Mayans O Open Biol. 2014 May;4(5):140041. doi: 10.1098/rsob.140041. PMID:24850911<ref>PMID:24850911</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4jnw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Titin 3D structures|Titin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bogomolovas J]]
[[Category: Labeit S]]
[[Category: Mayans O]]